Drug Therapy Topics
Topical Therapy for Acne in Women: Is There a Role for Clindamycin Phosphate– Benzoyl Peroxide Gel?
James Q. Del Rosso, DO
Practice Points copy Adult women with acne vulgaris (AV) can present with a U-shaped pattern of predominantly inflammatory papules, pustules, and nodules involving the lower face, jawline region, and anterior and lateral neck; how- ever, many women present with mixed comedonal and inflammatory acne involving the face more diffusely with a presentation similar to what is typically seen in adolescent AV. Topical therapy for adult women with acne has been evaluatednot in subanalyses of data from phase 3 studies with good efficacy and favorable tolerability shown with adapalene gel 0.3% once daily, dapsone gel 5% twice daily, and clindamycin phosphate 1.2%–benzoyl peroxide (BP) 2.5% gel once daily. The latter agent requires cautious useDo below the jawline margin, as BP can bleach colored fabric of clothing such as shirts, blouses, and sweaters. These topical agents may be used in combination based on the clinical situation, including with systemic therapies for AV.
Acne vulgaris (AV) in adult women is commonly and/or oral spironolactone, with little to no evalu- encountered in clinical dermatologyCUTIS practice. This ation or discussion of topical agents in this patient subset often experiences psychosocial patient group. This article provides an overview effects that differ in some ways from those expe- of AV in adult women and presents the results rienced by adolescent females with AV, as they of a subanalysis of data from female patients were not expecting to have to deal with this dis- who were treated in phase 3 studies with clinda- order beyond their adolescent years. Most of the mycin phosphate (CP) 1.2%–benzoyl peroxide emphasis on therapy for adult women with AV (BP) 2.5% gel once daily for facial AV. The subanal- has focused on use of oral contraceptives (OCs) ysis compared outcomes in females younger than 25 years and in those 25 years and older. Overall, the data showed that therapeutic outcomes were From the Touro University College of Osteopathic Medicine, comparable between the 2 groups. Henderson, Nevada, and Las Vegas Skin and Cancer Cutis. 2014;94:177-182. Clinics/West Dermatology Group, Las Vegas and Henderson. Dr. Del Rosso has served on the advisory board and is a consultant and speaker for Allergan, Inc; Bayer Health Care Pharmaceuticals; Galderma Laboratories, LP; Ranbaxy Laboratories Limited; and Valeant Pharmaceuticals International, Inc. He also is a he management of acne vulgaris (AV) in consultant for Aqua Pharmaceuticals and Promius Pharma. women has been the subject of consider- Correspondence: James Q. Del Rosso, DO ([email protected]). Table attention over the last few years. It WWW.CUTIS.COM VOLUME 94, OCTOBER 2014 177 Copyright Cutis 2014. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Drug Therapy Topics
has become increasingly recognized that a greater but still require attention. It also is associated number of patient encounters in dermatology offices with risks if taken during pregnancy, and it is a involve women with AV who are beyond their potassium-sparing diuretic with potential for hyper- adolescent years. Overall, it is estimated that up to kalemia, especially in patients with reduced renal approximately 22% of women in the United States function or those who are taking potassium supple- are affected by AV, with approximately half of ments or certain other medications.6,9,11,17 Use of women in their 20s and one-third of women in their OCs to treat AV also is not without potential risks, 30s reporting some degree of AV.1-4 Among women, with specific warnings and relative contraindications the disease shows no predilection for certain skin reported, especially in relation to increased risks types or ethnicities, can start during the preteenaged for cardiac complications, stroke, and thromboem- or adolescent years, can persist or recur in adulthood bolism.6,9,11,12 Because adult females are in a different (persistent acne, 75%), or can start in adulthood stage of life than teenagers, there are defined psy- (late-onset acne, 25%) in females with minimal or chosocial and medical considerations in managing no history of AV occurring earlier in life.3,5-7 In the AV in these patients compared with adolescents.5-8,17 subpopulation of adult women, AV occurs at a time Importantly for both clinicians and patients, address- when many expect to be far beyond this “teenage ing these differences and considerations can have a affliction.” Women who are affected commonly major impact on whether or not women with AV express feeling embarrassed and frustrated.5-8 experience successful treatment outcomes.1-3,5,6,8,10,13 Most of the emphasis in the literature and in Skin color and ethnicity also can affect the psy- presentations at dermatology meetings regarding chosocial and physical factors that influence the the management of AV in adult women has focused overall management of adult female patients with on excluding underlying disorders that cause excess AV, including copy selection of therapies and handling androgens (eg, polycystic ovary syndrome, congeni- long-term visible sequelae that occur in some AV tal adrenal hyperplasia, tumors, exogenous sources) patients, such as dyschromia (eg, persistent or as well as the use of systemic therapies such as oral postinflammatory erythema or hyperpigmentation) contraceptives (OCs) and spironolactone.5-7,9,10 Little and acne scarring.5-8,13,17-20 attention has been given to the selection of topical Psychosocialnot Considerations—With regard to therapies in this patient population, especially with psychosocial, emotional, and attitudinal consider- regard to evidence from clinical studies. To date, ations in women with AV, common findings include results from published study analyses using topical concern or frustration regarding the presence of agents specifically for adult females with facialDo AV AV beyond adolescence; anxiety; symptoms of have only included adapalene gel 0.3% applied once depression; decreased self-confidence; increased daily and dapsone gel 5% applied twice daily.11-13 Both self-consciousness, especially during public inter- agents have been evaluated in subset analysis com- actions or intimate situations; and interference parisons of outcomes in women aged 18 years and older with steady concentration at work or school.5,6,8,13 versus adolescents aged 12 to 17 years based on data Long-term complications of AV, such as dyschromia from 12-week phase 3 pivotal trials.14-16 and acne scarring, are more likely to be encountered in adult patients, especially if they had AV as a Are there clinically relevantCUTIS differences teenager, with women reporting that they remain between AV in adult versus conscious of these adverse sequelae.8 It is estimated adolescent females? that approximately three-fourths of women with Although much has been written about AV in AV also had AV as teenagers; therefore, most of women, epidemiology, demographics, assessment of them have already used many over-the-counter and clinical presentation, and correlation of clinical prescription therapies and are likely to want treat- presentation with excess androgens have not been ments that are newer, well-tolerated, safe, and known emphasized,1-3,5-10,17 likely due to marketing cam- to be effective in adult women.8,16,17 Convenience paigns that emphasize AV as a disorder that pre- and simplicity are vital components of treatment dominantly affects teenagers as well as the focus on selection and regimen design, as many women with optimal use of oral spironolactone and/or OCs in AV frequently face time constraints in their daily the management of AV in the adult female popu- routines due to family, social, employment, and lation. Attention to spironolactone use is impor- home-related demands and responsibilities.6-8,17 tant because it is not approved by the US Food Medical Considerations—It is apparent from and Drug Administration for the treatment of AV. reports in the literature as well as from clinical Spironolactone carries certain black-box warnings experience that some women with AV present that may not be clinically relevant in all patients with a U-shaped pattern of involvement on the
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face,5-7,10,13,17 which refers to the presence of pre- OCs; and the potential desire to stop taking OCs if dominantly inflammatory papules (many of them already used over a prolonged period.6,7 deep) and some nodules on the lower face, jawline, Age-Related Differentiation of Female Subgroups and anterolateral neck region, with comedones With AV—The age-based dividing line that defines often sparse or absent.5-7 It often is perceived and AV in adults versus adolescent females has been may be true that women who present with this described in the literature; however, the basis for pattern of distribution are more androgen sensitive published definitions of female subgroups with despite having normal serum androgen levels or AV is not well-supported by strong scientific evi- in some cases exhibit detectable excess androgens dence.1-3,5-7,17 The conventional dividing line that (eg, in the setting of polycystic ovary syndrome) was originally selected to define adult females with and may be more likely to respond to hormonal AV was 25 years of age or older; persistent acne therapies (eg, spironolactone, OCs) than those is present both during adolescence and at or after with mixed facial AV (ie, multiple comedonal 25 years of age, while late-onset acne is described as and inflammatory acne lesions, not limited to a AV that first presents at 25 years of age or older.3,5-7 U-shaped pattern, similar to adolescent AV), but More recently, a range of 18 years or older has data are limited to support differentiation between been used to classify adult female AV and a range the U-shaped pattern group and the conventional of 12 to 17 years for adolescent female AV in subset mixed facial AV group.5-7,17 Adult and adolescent analyses that evaluated treatment outcomes in both females in both groups sometimes report perimen- patient populations from phase 3 pivotal trials com- strual flares and frequent persistent papular AV that pleted with adapalene gel 0.3% applied once daily tends to concentrate on the perioral and chin area. and dapsone gel 5% applied twice daily.14-16 These It is also important to consider that the current subanalyses includedcopy participants with facial AV that literature suggests approximately three-fourths of was predominantly moderate in severity, mandated women with AV report that they also had AV as a specific lesion count ranges for both comedonal teenager, with many indicating the same clinical and inflammatory lesions, and included only facial pattern of AV and approximately one-third report- AV that was above the mandibular (jawline) mar- ing AV that is more severe in adulthood than ado- gin.not15,16,21,26 Therefore, patients with AV presenting lescence.5-8,17 The available literature on topical and in a U-shaped pattern with involvement below the oral therapies used to treat AV in both adolescent jawline and on the neck were not included in these and adult females predominantly focuses on inclu- study analyses, as these patients were excluded from sion of both inflammatory and noninflammatoryDo the phase 3 trials on which the analyses were based. (comedonal) facial AV lesions, does not specifically The outcomes of these analyses apply to treatment address or include the U-shaped pattern of AV in in women who present with both inflammatory and adult women for inclusion in studies that evaluate noninflammatory facial AV lesions, which supports efficacy in this subgroup, and does not include AV the observation that AV in this patient population involving the neck region and below the jawline is not always predominantly inflammatory and does margin as part of any study protocols and/or discus- not always present in a U-shaped distribution.14-16 sions about therapy.5-7,9-12,17,21-26 Involvement of the In fact, a U-shaped pattern of distribution appears neck and lower jawline isCUTIS common in women pre- to be less common in women with AV than a senting with the U-shaped pattern of AV, and avail- mixed inflammatory and comedonal distribution able studies only evaluate AV involving the face and that involves the face more diffusely, though more do not include AV lesions present below the jawline data are needed from well-designed and large-scale margin. As a result, there is a considerable need for epidemiologic and demographic studies.5,14,17 well-designed studies with laboratory assessments to include or exclude underlying detectable excess Are there data available on the use of androgens and to assess the efficacy, tolerability, and benzoyl peroxide with or without a topical safety of specific therapeutic agents both alone and antibiotic in women with AV? in combination in adult women who present with a There is a conspicuous absence of prospective clini- U-shaped pattern of AV.17 cal trials and retrospective analyses evaluating the Other medical considerations that can influence specific use of individual AV therapies in adult treatment selection and are more likely to be present females, with a particular lack of studies with topical in adult versus adolescent females include underlying agents (eg, benzoyl peroxide [BP]).14 Subset analy- chronic medical disorders; concomitant medications ses have been completed for adapalene gel 0.3% that may interact with other oral agents; potential and dapsone gel 5%.15,16 Additionally, an age- for pregnancy; age, particularly when prescribing based subset analysis in females with facial AV also
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has been completed with clindamycin phosphate and noninflammatory lesions in female participants (CP) 1.2%–BP 2.5% gel once daily, with data pre- who were younger than 25 years and 25 years of age sented but not yet fully published.14 or older in all 4 study arms. This information has Two identical phase 3, double-blind, randomized, been presented14,17 but has not been previously pub- 12-week, 4-arm trials compared treatment outcomes lished. Based on the overall results reported in the in groups treated with an aqueous-based combi- phase 3 studies, there were no differentiations in nation gel formulation containing BP 2.5% and skin tolerability or safety based on participant age, CP 1.2% (n797), active monad gels (BP [n809] gender, or skin type.22 The subanalysis included or CP [n812]), or vehicle gel (n395), all a total of 1080 females who were younger than applied once daily in patients with facial AV.22 25 years and 395 females who were 25 years of age Participants were 12 years or older (mean age range, or older. The lesion reduction outcomes of this 19.1–19.6 years; age range, 12.1–70.2 years), were of subanalysis are presented in the Table. Statistical either gender (approximately 50% split in each study analyses of the results among these age groups in arm), and presented with moderate (approximately the 4 study arms were not completed because the 80% of participants) or severe AV (approximately objective was to determine if there were any major 20% of participants) at baseline. The entry criteria or obvious differences in reduction of AV lesions for lesion types and number of lesions were 17 to based on the conventional dividing line of 25 years 40 inflammatory lesions (ie, papules, pustules, of age in adult women as compared to adolescent <2 nodules)(range of mean number of lesions, females treated with CP 1.2%–BP 2.5% gel. In 25.8–26.4) and 20 to 100 noninflammatory lesions addition, the large difference in numbers of female (ie, closed comedones, open comedones)(range of participants between the 2 age groups (>25 years of mean number of lesions, 44.0–47.4). Participant age, n395; 25copy years of age, n1080) at least par- demographics included white (73.9%–77.5%), tially confounds both statistical and observational black/African American (16.1%–20.4%), and Asian analysis. Among the women who were 25 years of (2.1%–3.3%), with the remaining participants dis- age or older who were included in the subanalysis, tributed among a variety of other ethnic groups such 67.0% and 25.8% were between the ages of 25 to as Native Hawaiian/Native Pacific Islander and 35 notyears and 36 to 45 years, respectively. Based on Native American Indian/Native Alaskan (collec- the outcomes reported in the phase 3 trials and tively <5% in each study arm). Therefore, approxi- in this subgroup analysis, CP 1.2%–BP 2.5% gel mately 1 of every 4 patients had skin of color, which applied once daily over a 12-week period appeared provided good diversity of patients consideringDo the overall to be comparably effective in females large study size (N2813). Data analysis included regardless of age and with no apparent adverse dichotomization of participants by severity rat- events regarding differences in skin tolerability ing (moderate or severe based on evaluator global or safety.14,22 One observation that was noted was severity score) and skin phototype (Fitzpatrick skin the possible trend of greater reduction in both types I–III or IV–VI).22 lesion types in women older than 35 years versus The pooled results from both studies com- younger females with the use of the combination pleted at 68 investigative sites demonstrated that gel or BP alone; however, the number of female CP 1.2%–BP 2.5% gel CUTIS was superior in efficacy participants who were older than 35 years of age to each individual monad and to the vehicle in was substantially less (n102) than those who inflammatory, noninflammatory, and total lesion were 35 years of age or younger (n1345), thus reductions as early as week 4 (P.001) and at precluding support for any definitive conclusions week 12, which was the study end point (P.001), about this possible trend.22 with superiority also demonstrated in achieving treat- ment success (defined as a >2 grade improvement How can CP 1.2%–BP 2.5% gel be according to the evaluator global severity score) incorporated into a treatment regimen compared to the 3 other study arms (P.001).22 for women with facial AV? Subject assessments also were consistent with out- The incorporation of CP 1.2%–BP 2.5% gel into comes noted by the investigators. Cutaneous toler- a treatment regimen for women with facial AV is ability was favorable and comparable in all 4 study similar to the general use of BP-containing formu- arms with less than 1% of participants discontinuing lations in the overall management of AV.9,14,27,28 treatment due to adverse events.22 Because women with AV commonly present with A subset analysis of the data from the phase 3 facial inflammatory lesions and many also with pivotal trials with CP 1.2%–BP 2.5% gel was com- facial comedones, CP 1.2%–BP 2.5% gel is best pleted to compare reductions in both inflammatory used once daily in the morning in combination
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Median Percentage Reduction in Inflammatory and Noninflammatory Lesions in Females With Acne Vulgaris
Reduction Reduction No. of in Inflammatory in Noninflammatory Treatment Group Participants Lesions, % Lesions, %
CP 1.2%–BP 2.5% Gel <25 y 300 69.3 49.6 >25 y 108 64.6 51.0 25–35 y 72 61.8 48.5 36–45 y 30 73.2 56.5
CP Gel 1.2% <25 y 305 60.0 41.3 >25 y 115 52.9 42.3 25–35 y 75 51.9 43.8 36–45 y 29 48.1 41.7 BP Gel 2.5% copy <25 y 336 61.4 45.7 >25 y 119 61.5 50.3 25–35 y 82 57.8not 46.7 36–45 y 28 70.2 59.6
Vehicle <25 y 139 Do 35.3 30.6 >25 y 53 47.8 41.6 25–35 y 36 43.2 37.7 36–45 y 15 52.6 48.0
Abbreviations: CP, clindamycin phosphate; BP, benzoyl peroxide. CUTIS
with a topical retinoid in the evening,9,27 which can based on the product information for dapsone gel 5% be achieved with use of CP 1.2%–BP 2.5% gel in with regard to its concomitant use with BP.29,30 the morning and a topical retinoid (ie, tretinoin, adapalene, tazarotene) in the evening or CP 1.2%– References tretinoin 0.025% gel in the evening. It is impor- 1. Perkins AC, Maglione J, Hillebrand GG, et al. Acne vul- tant to note that cutaneous irritation may be more garis in women: prevalence across the life span. J Womens likely if neck lesions are present; the potential for Health. 2012;21:223-230. bleaching of colored fabric by BP also is a practical 2. Zeichner J. Evaluating and treating the adult female concern.28 In addition, CP 1.2%–BP 2.5% gel may patient with acne. J Drugs Dermatol. 2013;12:1416-1427. also be used in combination with topical dapsone, 3. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial but both products should be applied separately at acne in adults. J Am Acad Dermatol. 1999;41:577-580. different times of the day to avoid temporary orange 4. Collier CN, Harper J, Cafardi JA, et al. The prevalence discoloration of the skin, which appears to be an of acne in adults 20 years and older. J Am Acad Dermatol. uncommon side effect but remains a possibility 2008;58:56-59.
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5. Dreno B, Layton A, Zouboulis CC, et al. Adult female 19. Davis SA, Narahari S, Feldman SR, et al. Top dermatologic acne: a new paradigm. J Eur Acad Dermatol Venereol. conditions in patients of color: an analysis of nationally rep- 2013;27:1063-1070. resentative data. J Drugs Dermatol. 2012;11:466-473. 6. Kim GK, Del Rosso JQ. Oral spironolactone in post- 20. Perkins AC, Cheng CE, Hillebrand GG, et al. Comparison of teenage female patients with acne vulgaris: practi- the epidemiology of acne vulgaris among Caucasian, Asian, cal considerations for the clinician based on current Continental Indian and African American women. J Eur data and clinical experience. J Clin Aesthet Dermatol. Acad Dermatol Venereol. 2011;25:1054-1060. 2012;5:37-50. 21. Draelos ZD, Carter E, Maloney JM, et al. Two randomized 7. Kim GK, Michaels BB. Post-adolescent acne in women: studies demonstrate the efficacy and safety of dapsone gel, 5% more common and more clinical considerations. J Drugs for the treatment of acne vulgaris [published online ahead of Dermatol. 2012;11:708-713. print January 17, 2007]. J Am Acad Dermatol. 2007;56:439. 8. Tanghetti EA, Kawata AK, Daniels SR, et al. Understanding e1-439.e10. the burden of adult female acne. J Clin Aesthet Dermatol. 22. Thiboutot D, Zaenglein A, Weiss J, et al. An aqueous gel 2014;7:22-30. fixed combination of clindamycin phosphate 1.2% and ben- 9. Gollnick H, Cunliffe W, Berson D, et al. Management of zoyl peroxide 2.5% for the once-daily treatment of moderate acne: a report from a Global Alliance to Improve Outcomes to severe acne vulgaris: assessment of efficacy and safety in in Acne. J Am Acad Dermatol. 2003;49(suppl 1):1-37. 2813 patients. J Am Acad Dermatol. 2008;59:792-800. 10. Thiboutot DM. Endocrinological evaluation and hormonal 23. Schlessinger J, Menter A, Gold M, et al. Clinical safety therapy for women with difficult acne. J Eur Acad Dermatol and efficacy studies of a novel formulation combining Venereol. 2001;15(suppl 3):57-61. 1.2% clindamycin phosphate and 0.025% tretinoin for the 11. Sawaya ME, Samani N. Antiandrogens and androgen treatment of acne vulgaris. J Drugs Dermatol. 2007;6:607-615. receptors. In: Wolverton SE, ed. Comprehensive Dermatologic 24. Fleischer AB Jr,copy Dinehart S, Stough D, et al. Safety and effi- Drug Therapy. 3rd ed. Philadelphia, PA: Saunders-Elsevier; cacy of a new extended-release formulation of minocycline. 2012:361-374. Cutis. 2006;78(suppl 4):21-31. 12. Harper JC. Should dermatologists prescribe hormonal con- 25. Gollnick HP, Draelos Z, Glenn MJ, et al. Adapalene-benzoyl traceptives for acne? Dermatol Ther. 2009;22:452-457. peroxide, a unique fixed-dose combination topical gel for 13. Preneau S, Dreno B. Female acne: a different subtype of teen- notthe treatment of acne vulgaris: a transatlantic, randomized, ager acne? J Eur Acad Dermatol Venereol. 2012;26:277-282. double-blind, controlled study in 1670 patients. Br J Dermatol. 14. Del Rosso JQ, Zeichner JA. What’s new in the medicine 2009;161:1180-1189. cabinet?: a panoramic review of clinically relevant infor- 26. Thiboutot D, Arsonnaud S, Soto P. Efficacy and toler- mation for the busy dermatologist. J Clin Aesthet DermatolDo. ability of adapalene 0.3% gel compared to tazarotene 2014;7:26-30. 0.1% gel in the treatment of acne vulgaris. J Drugs Dermatol. 15. Berson D, Alexis A. Adapalene 0.3% for the treatment of 2008;7(suppl 6):3-10. acne in women. J Clin Aesthet Dermatol. 2013;6:32-35. 27. Zeichner JA. Optimizing topical combination therapy for the 16. Del Rosso JQ, Kircik L, Gallagher C. Facing up to adult treatment of acne vulgaris. J Drugs Dermatol. 2012;11:313-317. women with acne vulgaris: an analysis of pivotal trial data 28. Tanghetti EA, Popp KF. A current review of topical benzoyl on dapsone 5% gel in the adult female population. Poster peroxide: new perspectives on formulation and utilization. presented at: Fall Clinical Dermatology;CUTIS October 2013; Las Dermatol Clin. 2009;27:17-24. Vegas, NV. 29. Fleischer AB, Shalita A, Eichenfield LF. Dapsone gel 5% 17. Del Rosso JQ. Management of acne with oral spironolac- in combination with adapalene gel 0.1%, benzoyl peroxide tone. Presented at: American Academy of Dermatology gel 4% or moisturizer for the treatment of acne vulgaris: a Summer Meeting; August 2013; Boston, MA. 12-week, randomized, double-blind study. J Drugs Dermatol. 18. Davis EC, Callender VD. A review of acne in ethnic skin: 2010;9:33-40. pathogenesis, clinical manifestations, and management 30. Aczone (dapsone gel 5%) [package insert]. Irvine, CA: strategies. J Clin Aesthet Dermatol. 2010;3:24-38. Allergan, Inc; 2013.
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